Journal
CANCER RESEARCH
Volume 75, Issue 22, Pages 4688-4696Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-15-0892
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Funding
- Molecular Pharmacology & Chemistry Program Core
- Radiological Society of North America Research Resident Grant [RR1350]
- Rebecca and Nathan Milikowsky Prostate Cancer Foundation Young Investigator Award
- Prostate Cancer Foundation
- IMRAS MSKCC institutional grant
- NIH [P50CA091956MAYOCLINIC SPORE, P50CA09262 MSKCC SPORE, P30 CA008748]
- T.J. Martell Foundation
- Howard Hughes Medical Institute
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Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival. (C) 2015 AACR.
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